Antibody-drug conjugates (ADC), also known as immunoconjugates, are targeted chemotherapeutic molecules which combine ideal properties of both antibodies and cytotoxic drugs by targeting potent cytotoxic drugs to antigen-expressing tumor cells (Teicher, B. A. (2009) Curr. Cancer Drug Targets 9:982-1004), thereby enhancing the therapeutic index by maximizing efficacy and minimizing off-target toxicity (Carter, P. J. and Senter P. D. (2008) The Cancer Jour. 14(3):154-169; Chari, R. V. (2008) Acc. Chem. Res. 41:98-107. ADC comprise a targeting antibody covalently attached through a linker unit to a cytotoxic drug moiety. Immunoconjugates allow for the targeted delivery of a drug moiety to a tumor, and intracellular accumulation therein, where systemic administration of unconjugated drugs may result in unacceptable levels of toxicity to normal cells as well as the tumor cells sought to be eliminated (Polakis P. (2005) Curr. Opin. Pharmacol. 5:382-387).
The concept of ADC in cancer therapy has been expanded into antibacterial therapy, where the drug portion is an antibiotic, resulting in antibody-antibiotic conjugate (AAC). An anti-WTA monoclonal antibody was conjugated by a covalent linker attachment to one or more rifamycin-type antibiotic moieties (Lehar, S. et al (2015) “Novel antibody-antibiotic conjugate eliminates intracellular S. aureus” Nature 527(7578) 323-328; Staben, L. R., et al (2016) “Targeted drug delivery through the traceless release of tertiary and heteroaryl amines from antibody-drug conjugates” Nature Chemistry 8 (12):1112-1119; Zhou, C., et al (2016) “Pharmacokinetics and pharmacodynamics of DSTA4637A: A novel THIOMAB™ antibody antibiotic conjugate against Staphylococcus aureus in mice” MABS 8 (8):1612-1619; WO 2014/194247), and other antibiotics (WO 2014/193722). It was demonstrated that intracellular reservoirs of S. aureus in mice comprise a virulent subset of bacteria that can establish infection even in the presence of vancomycin. The anti-WTA rifamycin conjugate is a novel therapeutic that effectively kills intracellular S. aureus. This antibody-antibiotic conjugate (AAC) consists of S. aureus targeting antibody conjugated to a highly efficacious antibiotic is activated only after it is released in the proteolytic environment of the phagolysosome. The antibody-antibiotic conjugate is superior to vancomycin for treatment of bacteremia and provides direct evidence that intracellular S. aureus represents an important component of invasive infections.